Tadalafil Nanoemulsion Mists for Treatment of Pediatric Pulmonary Hypertension via Nebulization

Oral tadalafil (TD) proved promising in treating pediatric pulmonary arterial hypertension (PAH). However, to ensure higher efficacy and reduce the systemic side effects, targeted delivery to the lungs through nebulization was proposed as an alternative approach. This poorly soluble drug was previously dissolved in nanoemulsions (NEs). However, the formulations could not resist aqueous dilution, which precluded its dilution with saline for nebulization. Thus, the current study aimed to modify the previous systems into dilutable TD-NEs and assess their suitability for a pulmonary application. In this regard, screening of various excipients was conducted to optimize the former systems; different formulations were selected and characterized in terms of physicochemical properties, nebulization performance, stability following sterilization, and biocompatibility.

Results showed that the optimal system comprised of Capmul-MCM-EP:Labrafac-lipophile (1:1) (w/w) as oil, Labrasol:Poloxamer-407 (2:1) (w/w) as surfactant mixture (S_mix) and water. The optimum formulation P2_TD resisted aqueous dilution, exhibited reasonable drug loading (2.45 mg/mL) and globule size (25.04 nm), acceptable pH and viscosity for pulmonary administration, and could be aerosolized using a jet nebulizer. Moreover, P2_TD demonstrated stability following sterilization and a favorable safety profile confirmed by both in-vitro and in-vivo toxicity studies. These favorable findings make P2_TD promising for the treatment of pediatric PAH.

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Materials

Tadalafil (TD) was purchased from Radiant Pharma (Mumbai, India). Labrasol^® (Caprylocaproyl macrogol-8 glycerides EP, hydrophilic–lipophilic balance (HLB) = 14), Transcutol^® HP (Highly purified Diethylene glycol monoethyl ether EP/NF) and Labrafac^TM-lipophile WL1349 (Medium chain fatty acid triglyceride JPE) were kind gifts from Gattefossé (Lyon, France). Capmul^® MCM EP (Glycerol monocaprylocaprate, a mixture of medium chain length monoglyceride (60%) and diglyceride (35%), consisting of 83% w/w caprylic acid (C₈) and 17% w/w capric acid (C₁₀)) was donated as a gift from Abitec Corporation (Janesville, WI, USA). Cremophor^® EL (Polyoxyl 35 castor oil USP, HLB = 12–14), Cremophor^® RH40 (Kolliphor Rh 40) (Polyoxyl 40 hydrogenated castor oil USP/NF, HLB = 14–16), and Poloxamer-407 (Lutrol^® F 127, HLB = 18–23) was obtained from BASF (Ludwigshafen, Germany). Tween-80 (HLB = 15) and propylene glycol were provided by El-Nasr Pharmaceutical Chemicals (Cairo, Egypt). Polyethylene glycol 400 (PEG 400) was purchased from Sisco Research Laboratories Pvt. Ltd. (Mumbai, India). Human lung adenocarcinoma epithelial cell line (A549) was obtained from the American Type Culture Collection (ATCC) (Saint Cloud, MN, USA) through the Tissue Culture Unit, Egyptian Organization for Biological Products and Vaccines, Vacsera (Cairo, Egypt). Dulbecco’s Modified Eagle’s Medium (DMEM) was purchased from Lonza (Biowhittaker, Belgium) supplemented with 10% fetal bovine serum (FBS) (Lonza, Biowhittaker, Belgium), 1% (v/v) L-glutamine (Lonza, Biowhittaker, Belgium) and 1 g/L glucose (Lonza, Biowhittaker, Belgium). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) was purchased from Serva (Heidelberg, Germany). Ketamine^® (Ketamine hydrochloride 50 mg/mL) was purchased from Sigmatec Pharmaceutical Industries (Giza, Egypt). Xyla-ject^® (Xylazine hydrochloride 20 mg/mL) was purchased from Adwia Pharmaceuticals (Cairo, Egypt). Lactate dehydrogenase (LDH) and protein cytotoxicity detection kits were obtained from Roche Diagnostics (Indianapolis, IN, USA). All other chemicals and reagents were of analytical grade.

Elbardisy, B.; Boraie, N.; Galal, S. Tadalafil Nanoemulsion Mists for Treatment of Pediatric Pulmonary Hypertension via Nebulization. Pharmaceutics 2022, 14, 2717. https://doi.org/10.3390/pharmaceutics14122717